Phenyl-substituted, nitrogen-containing five-ring heteroaryls are described in WO 2005/090333 and US 2006/0100204 for inhibiting cytokine production and hence for treating inflammatory diseases and in WO 2008/003770 for inhibiting signal enzymes and hence for the treatment of diseases that are characterised by excessive or abnormal cell proliferation. Further phenyl-substituted five-ring heteroaryls for inhibiting cytokines are described in WO 2007/075896.
The aim of the present invention is to indicate new phenyltriazoles which may be used for the prevention and/or treatment of diseases characterised by excessive or abnormal cell proliferation. The phenyltriazoles according to the invention are distinguished by their great inhibitory effect on B-Raf V600E and their high potency against tumour cells, e.g. melanoma cells, which is achieved by the inhibition of B-Raf V600E. In addition to the inhibitory effect and cell potency the compounds additionally have good pharmacokinetic properties and good solubility. As a result of this overall profile, the compounds according to the invention are suitable for the development of a drug.
The RAS-RAF-MAPK (mitogen-activated protein kinase) signaling pathway plays a critical role in transmitting proliferation signals generated by the cell surface receptors and cytoplasmic signaling elements to the nucleus. Constitutive activation of this pathway is involved in malignant transformation by several oncogenes. Activating mutations in RAS occur in approximately 15% of cancers, and recent data has shown that B-RAF is mutated in about 7% of cancers (Wellbrock et al., Nature Rev. Mol. Cell. Biol. 2004, 5:875-885), identifying it as another important oncogene in this pathway. In mammals, the RAF family of serine/threonine kinases comprises three members: A-RAF, B-RAF and C-RAF. However, activating mutations have so far been only identified in B-RAF underlining the importance of this isoform. It is believed that B-RAF is the main isoform that couples RAS to MEK, and that C-RAF and A-RAF signal to ERK only to fine-tune cellular responses (Wellbrock et al., Nature Rev. Mol. Cell. Biol. 2004, 5:875-885). The most common cancer mutation in B-RAF results in a valine to glutamic acid exchange at position 600 of the protein (V600E), which dramatically enhances B-RAF activity, presumably because its negative charge mimics activation loop phosphorylation (Wan et al., Cell 2004, 116: 855-867). The highest incidence of B-RAF V600 mutations occurs in malignant melanoma (38%), thyroid cancer (38%), colorectal cancer (10%), bilary tract cancer (12%) and ovarian cancer (12%), but they also occur at a low frequency in a wide variety of other cancers (frequencies of mutations according to COSMIC (Catalogue Of Somatic Mutations In Cancer; Wellcome Trust Sanger Institute) release v49, 29, Sep. 2010). Literature supported the hypothesis that B-RAFV600E mutated tumour cells seem to rely heavily on the continued activation of this pathway—a phenomenon termed “oncogene addiction”—whereas normal B-RAFwt cells use a broader range of signals. This provides an Achilles' heel that can be exploited therapeutically by treating patients with somatically mutated B-RAFV600E using orally available B-RAF inhibitors.
The key role of B-RAFV600E in aberrant ERK signaling and consequently oncogenesis has been demonstrated in several independent experimental approaches such as overexpression of oncogenic/mutated B-RAF in vitro and in vivo (Wan et al., Cell 2004, 116: 855-867; Wellbrock et al., Cancer Res. 2004, 64: 2338-2342), siRNA knock-down in vitro (Karasarides et al., Oncogene 2004, 23: 6292-6298) or in inducible short-hairpin RNA xenograft models where gain-of-function B-RAF signaling was found to be strongly associated with in vivo tumorigenicity (Hoeflich et al., Cancer Res. 2006, 66: 999-1006).
Treatment of B-RAFV600E mutated melanoma or colon carcinoma cells induces a B-RAF inhibition phenotype (e.g. reduction of phospho-MEK and phospho-ERK levels, reduction of cyclin D expression and induction of p27 expression). Consequently, these cells are locked in the G1-phase of the cell cycle and do not proliferate.